Study Supports Use of Base-Edited CAR7 T Cells for Relapsed T-Cell ALL, But Further Investigation Is Needed

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Researchers noted that the therapy remains risky, owing to the substantial immunosuppressive and cytopenic effects of the trial protocol and the risks that immune-cell manipulation carries.

The interim results of a phase 1 study examining the use of base-edited chimeric antigen receptor (CAR) T cells that recognize CD7 antigens (CAR7) in treating patients with relapsed T-cell acute lymphoblastic leukemia (ALL) supports further research but indicates the potential risks of immunotherapy-related complications, according to the authors of a study published in The New England Journal of Medicine.

During the trial, the investigators used base editing to create universal CAR T cells. To express a CAR that specifically recognizes CD7 antigens—a protein in T-cell ALL—the researchers transduced healthy volunteer donor T cells with the use of a lentivirus. Through base editing, the investigators inactivated 3 genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease, respectively, according to the study authors.

Through base editing, the investigators inactivated 3 genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease, respectively. Image Credit: Adobe Stock - LASZLO

Through base editing, the investigators inactivated 3 genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease, respectively. Image Credit: Adobe Stock - LASZLO

The study began in April 2022 at a hospital in London and featured a study population of 10 participants who were between the ages of 6 months and 16 years with relapsed or refractory CD7+ T-cell cancer that was quantifiable in bone marrow, according to the study authors. The published study results focuses on the first 3 patients included in the study.

Patient 1 was a 12-year-old girl with T-cell ALL who had a poor response with induction chemotherapy but achieved remission after multiple lines of additional treatment. She was aged 13 years when she received an infusion of 50×106 BE-CAR7 cells (0.7×106 per kilogram CAR7 T cells and <5×104 per kilogram TCRαβ T cells), and her bone marrow showed 0.3% blasts, according to the authors.

On day 27 of observation, patient 1’s bone marrow was hypocellular and in morphologic remission, with undetectable minimum residual disease (MRD), although multiple adverse effects (AEs) occurred. The patient began conditioning for a second stem-cell transplant on day 43, and despite more AEs developing and being treated, her bone marrow remained in remission, and she was discharged 52 days after stem-cell transplantation, the study authors wrote.

Patient 2 was a boy aged 13 years who received a diagnosis of cortical T-cell ALL 3 years prior to enrollment and had relapsed while receiving maintenance treatment; he had refractory disease which manifested as persistent cytopenia with more than 80% blasts in bone marrow, which were all expressing CD7, according to the study authors.

The patient underwent lymphodepletion and was infused with 1×106 BE-CAR7 T cells per kilogram. Imaging and analysis in the coming days incidentally revealed maxillary Aspergillus fumigatus infection, the study investigators explained. A bone marrow assessment on days 19 and 25 revealed hypocellular marrow in morphologic and flow remission, but with signs of MRD, the investigators noted. After undergoing lung consolidation and hypoxic respiratory deterioration associated with overlapping Aspergillus niger infection led to palliation and death of the patient on day 33.

Patient 3 was a 15-year-old boy who underwent a first allogeneic stem-cell transplantation to treat mixed-phenotype acute leukemia in 2016; after MRD was discovered in his bone marrow, he received 2 donor lymphocyte infusions. However, the disease relapsed in the bone marrow, and the patient’s disease transitioned to CD7+ T-cell ALL. Lymphodepletion was administered and BE-CAR7 T cells were infused at a dose of 0.9×106 per kilogram, according to the investigators. The patient also had some AEs, but BE-CAR7 T-cells were detected in his blood and bone marrow, and at day 28 an assessment revealed complete remission.

Additionally, the researchers noted in the study that their research supports base editing as a therapeutic approach and that the study results are consistent with previous studies showing the antileukemic effects of allogeneic CAR T cells which can secure remission and deep clearance of T-cell ALL.

Notably, the researchers explained that such treatment is risky, owing to the substantial immunosuppressive and cytopenic effects of the trial protocol and the risks that immune-cell manipulation carries.

“Similar studies in the United States are in prep­aration,24 as well as a related approach using anti-CD33 CAR T cells25 for deep conditioning ahead of allogeneic stem-cell transplantation for relapsed acute myeloid leukemia in Europe,” the study authors wrote, emphasizing the need for continued research on the subject.

Reference

Chiesa R MD, Georgiadis C PhD, Syed F PhD, et al. Base-edited CAR7 T cells for relapsed T-cell acute lymphoblastic leukemia. N Engl J Med. 2023. doi:10.1056/NEJMoa2300709

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